1. Field of the Invention
The present invention relates to a composition which is useful for inducing weight loss in humans and to a treatment for obesity. More specifically, the invention is directed to a composition containing aspirin, caffeine and ephedrine and use of this composition for producing weight loss.
2. Description of the Background
Western society is increasingly concerned with personal weight and appearance. Diets and weight loss programs are extensively advertised and utilized by a large segment of Western society with varying degrees of effectiveness. There is a continuing search for new and effective means to facilitate weight loss.
Obesity, originally presumed to result from simple overeating or the combination of overeating with inactivity, has more recently been attributed to a genetic predisposition in combination with poor diet and exercise habits. It has been suggested that predisposition to obesity is associated with a defect in the sympathetic nervous system. This defect is manifested as a high efficiency in food utilization and a reduced thermogenic response to food intake. In normal persons, food intake results in a thermogenic response, that is, an increase in body temperature in which the caloric content of food is expended as heat. Some studies suggest that persons with a genetic predisposition to obesity are metabolically more efficient than lean persons, storing excess caloric energy as body fat. In obese persons, thermogenic defects may make a significant contribution to weight gain in the absence of controlled food intake. Calories not expended as heat are stored as excess weight. See Dulloo, A. G. and Miller, D. S., Wld. Rev. Nutr. Diet., vol. 50, pp. 1-56, 1987.
Pharmaceutical compositions have been developed with the purpose of stimulating thermogenesis and thereby inducing weight loss. Ephedrine stimulates thermogenesis in laboratory animals, presumably by stimulating brown adipose tissue. In theory, catecholamines activate thermogenesis in brown adipose tissue in animals by binding adrenergic receptors (Buckowiecki, L., Jahjah, L., and Follea, N., International Journal of Obesity, vol. 6, pp. 343-350, 1982). Numerous studies have been published on the thermogenic response of humans and mammals to ephedrine treatment (See for example Morgan, J. B., York, D. A., Wasilewska, A. and Portman, J., Br. J. Nutr., vol. 47, pp. 21-32, 1982; Dulloo, A. G. and Miller, D. S., Br. J. Nutr., vol. 52, pp. 179-196, 1984; Himms-Hagen, J., Seminars in Medicine of the Beth-Israel Hospital, Boston, vol. 311, no. 24, pp. 1549-1558, 1984; Pasquali, R., Cesari, M. P. Melchionda, N., Stefanini, C., Raitano, A. and Labo, G., International Journal of Obesity, vol. 11, pp. 163-168, 1987; Astrup, A., Lundsgaard, C., Madsen, J. and Christensen, N. J., The American Journal of Clinical Nutrition, vol. 42, pp. 83-94, 1985 and Astrup, A., Bulow, J., Madsen, J. and Christensen, N. J., Journal of the American Physiological Society, pp. E507-E515, 1985). The anorectic effect of ephedrine has also been investigated in rats (Zarrindast, M. R., Hosseini-Nia, T. and Farnoodi, F., Gen. Pharmac., vol. 18, no. 5, pages 559-561, 1967). Ephedrine, used alone, results in increased thermogenesis, but also undesirable side effects in man, such as elevated blood pressure and tremors.
The thermogenic response to ephedrine in animals varies with the type of animal model studied. Dulloo and Miller (British Journal of Nutrition, loc. cit.) have studied the thermogenic properties of six sympathomimetic drugs in both mice and rats. The six drugs studied were ephedrine, methoxyphenamine, yohimbine, tranylcypromine, amitriptyline, iprindole and theophylline. The metabolic response of various mice and rat models differed with the respective drugs. For example, in mice made obese by chemical lesioning in the hypothalamus, all of the drugs with the exception of theophylline caused a reduction in body fat without loss of body protein. Similarly, all six drugs with the exception of theophylline resulted in a state of negative energy balance by means of a thermogenic effect. In contrast, in mice made obese by feeding a high protein, high fat diet, all seven drugs caused a negative energy imbalance. In genetically obese mice only ephedrine and tranylcypromine were found to have thermogenic activity. A similar variability in physiological effect was seen in the rat models.
The activity of thermogenic drugs in humans has been postulated to involve brown adipose tissue. However, this proposed mechanism of action has never been verified in humans.
Studies have also been reported investigating combinations of ephedrine with additional compounds such as caffeine. In 1972, a composition containing ephedrine, caffeine and phenobarbitol was noted as inducing loss of appetite and weight loss in humans. This composition, popularly known as the "Elsinore pill" was widely prescribed. However, serious side effects such as cutaneous reactions (tremors) were reported with this composition. Ephedrine/caffeine compositions without the presence of phenobarbitol were also been investigated in attempts to reduce the side effects of the Elsinore pill. However, patients receiving this "modified Elsinore pill" continue to suffer from tremors similar to the effects seen with the Elsinore pill (Malchow-Moller, A., Larsen, S., Hey, H., Stokholm, K. H., Juhl, E. and Quaade, F., International Journal of Obesity, vol. 5, pp. 183-187, 1981).
More recent studies of the thermogenic effects in humans of mixtures of ephedrine and methylxanthines, such as caffeine and theophylline, have been reported by Dulloo and Miller (American Journal of Clinical Nutrition, vol. 43, pp. 388-394, 1986 and International Journal of Obesity, vol. 10, pp. 467-481, 1986). These studies suggest that ephedrine/methylxanthine mixtures are more effective than ephedrine given alone. Methylxanthines are reported as potentiating the thermogenic anti-obesity effect of ephedrine leading to normalization of body weight and body composition. However, reports have also been published suggesting that caffeine has no potentiating effect on the action of ephedrine (Cesari, M. P., Pasquali, R., Casimirri, F., Melchionda, N., Stefanini, C. and Raitano, A., Ist. Clin. Med. and Gastroenterol., Univ. Alma Mater, S. Orsola Hospital, Bologna, Italy).
Studies reporting the thermogenic effect of ephedrine/etilefrine (Pasquali, R., Cesari, M.P., Besteghi, L., Melchionda, N. and Balestra, V., International Journal of Obesity, vol. 11, Supplement 3, pp. 23-26, 1987) and ephedrine/aspirin (Dulloo, A. G. and Miller, D. S., Am. J. Clin. Nutr., vol. 45, pp. 564-569, 1987) have also been reported. Results obtained with ephedrine/etilefrin were inconclusive. Aspirin appears to potentiate the thermogenic effects of ephedrine.
A need continues to exist for improved weight loss compositions which are safe, effective and exhibit reduced side effects in humans. Studies on the thermogenic and physiological effects of ephedrine and other compounds in rats and mice give varying results which cannot be directly applied to the use of these compounds in humans. The function of brown adipose tissues in humans is only speculative. The thermogenic effect demonstrated in animals has been postulated to proceed by means of brown adipose tissue in animals, an effect which cannot be directly applied to human treatment in view of the variable effects seen with sympathimometic drugs in animal studies. A new approach to weight loss composition and methods for use in humans is needed.